Ambrisentan and darusentan were reported firstly in J. Med. Chem. 1996, 39, 2123-2128, as a selective antagonist for endothelin receptor A. Since then, their pharmacological properties have been further researched, as published in J. Med. Chem. 1996, 39, 2123-2128, U.S. Pat. No. 5,932,730, and WO 2009/017777 A2. As represented in formula (I), when R is methyl, its English name is (+)-ambrisentan, and its English nomenclature is (S)-2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid; when R is methoxy, its English name is (+)-darusentan, and its English nomenclature is: (S)-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropanoic acid. Now, the ambrisentan has been approved by FDA in the United states under the trade name of Letairis to administrate orally for treating pulmonary hypertension. Darusentan may become a new drug for resistant hypertension.
The existing synthesis technique of ambrisentan or darusentan includes the Darzens reaction of benzophenone and methyl chloroacetate to produce a racemic epoxy compound, and ring opening the racemic epoxy compound under catalysis of boron trifluoride ether solution to obtain a prochiral alcohol, and further substitution reaction and hydrolysis reaction to obtain ambrisentan or darusentan. The existing method for obtaining optically pure (+)-ambrisentan or (+)-darusentan mainly relies on a resolving technique. For example, the prochiral alcohol is resolved by L-proline methyl ester or R-phenethylamine, see WO 2010/070658 A2 and WO 2011/004402 A2. It is well known that resolving of chiral drug has lower availability for materials, causing cost increase, and limiting the industrialized application of the product.